The 13q and 11q B‐cell chronic lymphocytic leukaemia‐associated regions derive from a common ancestral region in the zebrafish

Abstract

SummaryLoss of the long arm of chromosomes 11 and 13 is the most consistent cytogenetic abnormalities for patients with B‐cell chronic lymphocytic leukaemia (B‐CLL). They suggest the presence of as yet unidentified tumour suppressor genes within well‐defined minimal‐deleted regions (MinDRs). We have identified 38 orthologues of the human genes in MinDRs in zebrafish cDNA and syntenic regions for the human deletions in the zebrafish genome. One region on chromosome 9 in the zebrafish genome is of potential interest. Within chromosome 9, five genes and two microRNAs were identified with shared synteny to the MinDRs in B‐CLL (two genes to human chromosome 11, three to human chromosome 13 and two chromosome 13 microRNAs). The critical region on zebrafish chromosome 9 maps to the MinDR for both human chromosomes, suggesting a common ancestry for B‐CLL tumour suppressor genes. Target‐selected mutagenesis to identify zebrafish mutants with knock‐outs of genes in this region will allow analysis of their in vivo potential for lymphoproliferation and may define causative genes for B‐CLL within human chromosomes 11q and 13q. Our study provides an explanation for involvement of both 11q and 13q in B‐CLL and the potential to develop animal models for this common lymphoproliferative disorder.

Chronic lymphocytic leukemia: interplay between noncoding RNAs and protein-coding genes

“…29 Interestingly, a critical synthenic region on zebrafish chromosome 9 maps to the minimal deleted region in CLL patients on both human chromosomes, suggesting a common ancestry for the 2 clusters of miRNAs miR-15a/miR-16-1 and miR-34b/miR-34c. 30 Investigators have delineated the pathogenic role played by the miR-34 family in tumorigenesis in general and CLL in particular by analyzing the transcriptome induced by overexpression of miR-34, which is highly similar to that observed with expression of the P53 tumor suppressor. In fact, the transcriptome is highly enriched for genes that regulate cell-cycle progression, apoptosis, DNA repair, and angiogenesis.…”

Molecular Pathology of Chronic Lymphocytic Leukemia

“…MiR-34a is transcriptionally induced by p53 and directly targets CDK6, CCND1, CDK4, CCNE2, and MET [25] expression in patients with CLL [26]. Furthermore, there appears to be a common ancestry for the miR-15a/miR-16-1 and miR-34b/miR-34c clusters [27]. Investigators have analyzed the transcriptome induced by overexpression of miR-34 in CLL.…”

miR Deregulation in CLL

“…However, it has been proved that the loss of the long arm of chromosome 11 includes the region where the miR-34b/c cluster is located (Auer RL et al 2007), while deletion of 17p leads to abrogation of the p53 tumor suppressor (Merkel O et al 2010) and 13q deletion involves miR15a/16- down-regulation. To establish the possible existence of molecular interactions between these chromosomal alterations, we investigated if the miR-15a/16-1 cluster, tumor protein p53, and miR-34b/c cluster are connected in a molecular pathway that could explain the prognostic implications (aggressive vs indolent form) of 11q, 17p, and 13q deletions in CLL (Fabbri M et al 2011).…”